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Dipeptidyl peptidase 4 restoration facilitates anti-tumor immunity in KRAS–LKB1–mutant lung cancer

ABSTRACT: KRAS proto-oncogene, GTPase (KRAS)-liver kinase B1 (LKB1)-mutant (KL) non-small cell lung cancer (NSCLC), characterized by a profoundly immunosuppressive tumor microenvironment (TME), is highly resistant to immune checkpoint inhibitors (ICIs). Despite their high tumor mutation burden, KL tumors exhibit low programmed cell death ligand 1 (PD-L1) expression, reduced immune cell infiltration, and suppressed immune signaling pathways. Through systematic genomic analyses, we found that LKB1 loss suppresses dipeptidyl peptidase 4 (DPP4) expression and activity in KRAS-mutant lung cancer. Therefore, we evaluated the therapeutic potential of restoring DPP4 function to improve the immune response in KL lung cancer using patient-derived tumor samples and syngeneic mouse models. Restoration of DPP4 expression reprogrammed the TME and significantly increased immune-related gene signatures, including those involved in T cell migration and natural killer (NK) cell activation. Indeed, DPP4 restoration in three-dimensional microfluidic models enhanced NK cell chemotaxis and activity in targeting tumor spheroids. Furthermore, DPP4 restoration in syngeneic KL murine models synergized with anti-PD-1 therapy to achieve significant tumor regression. These findings suggest that LKB1 loss suppresses DPP4 expression, contributing to the immunosuppressive characteristics of the TME in KL-NSCLC cells, whereas, restoring DPP4 expression promotes NK cell recruitment, facilitates immune activation, and enhances the effects of anti-PD-1 therapy. These results highlight DPP4 as a key immune modulator and a promising therapeutic target, offering a novel strategy to overcome immune resistance and enhance immunotherapy outcomes in this challenging subset of lung cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302247 | GEO | 2025/11/18

REPOSITORIES: GEO

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			Action	DRS
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	GSE302247_gene-FPKM_name_v3.1.txt.gz	Txt
	GSE302247_gene-featureCount-else-int_name_v3.1.txt.gz	Txt

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Project description:Purpose: Mutations in STK11 (LKB1) occur in 17% of lung adenocarcinoma (LUAD) and drive a suppressive (cold) tumor immune microenvironment (TME) and resistance to immunotherapy. The mechanisms underpin the establishment and maintenance of a cold TME in LKB1 mutant LUAD remain poorly understood and the identification of downstream effectors is critical to inform therapeutic strategies to invigorate antitumor immunity. In this study, we investigated the association between inactivation of AMPK, one of the downstream substrates of LKB1, and immune evasion in human LUAD as well as the causal role of AMPK on TME in genetically engineered mouse model (GEMM) of LUAD. Experimental Design: We modeled AMPK inactivation in vivo using GEMM by deleting both AMPKα1 (Prkaa1) and AMPKα2 (Prkaa2) in KrasG12D-driven LUAD (KAA). Furthermore, we investigated the impact of AMPK inactivation on immune cell infiltration and global gene-expression programs of murine LUAD. Gene expression signature from AMPK-deficient murine LUAD was further compared to that of Lkb1 deficient murineLUAD as well as human LUAD with either LKB1 mutation or attenuated AMPK phosphorylation. Results: Inactivation of both AMPKα1 and AMPKα2 accelerates KrasG12D-driven LUAD. AMPK-deficient tumors are characterized with reduced infiltration of CD8+/CD4+ T cells and gene signatures associated with compromised immune microenvironment, which resembles LKB1-deficient murine and human LUAD (KL) as well as LKB1-wildtype LUAD with reduced AMPK phosphorylation. Attenuation of the MHC Class 1 component ß2 microglobulin (ß2M) was identified as a shared feature in KL and KAA murine LUAD as well as in human LUAD with either LKB1 mutations or reduced AMPK phosphorylation. Furthermore, reactivation of AMPK by expression of constitutive active form of AMPKα1 leads to restoration of ß2M level in LKB1 mutant LUAD cells. Conclusions: The results identify attenuation of the LKB1 substrate AMPK as an important mechanism for decreased MHC Class 1 expression and immune evasion in LKB1 mutant LUAD. Translational relevance: LKB1 loss-of-function mutations rank as the third most common genetic alterations found in lung adenocarcinoma and associated with immune evasion. In the current study, on the basis of GEMM of LUAD we established the causal relationship between inactivation of the LKB1 substrate AMPK and immune evasion. Furthermore we find that the status of AMPK phosphorylation is more sensitive than LKB1 mutation in predicting impaired tumor immune microenvironment and likely also for the resistance to immunotherapy. The results also suggest that restoration of AMPK activity could increase the number of patients benefiting from immunotherapy.

Project description:Background: LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Inactivation of Lkb1 accelerates the growth and progression of oncogenic KRAS-driven lung tumors in mouse models. However, the molecular mechanisms by which LKB1 constrains lung tumorigenesis and whether the aggressive cancer state that stems from Lkb1 deficiency can be reverted remains unknown. By bulk gene expression profiling, Lkb1 restoration promotes the expression of markers and functions of alveolar type II cells, suggesting that LKB1 may govern a cell-state transition within the neoplastic epithelial compartment. Purpose: To determine whether the restoration of Lkb1 drives changes in cell state and/or abundance within established oncogenic KRAS-driven lung tumors. Approach: To control LKB1 function in vivo, we generated an Lkb1XTR allele, which enables Cre-mediated disruption of Lkb1 expression during tumor development and subsequent FLPo-ERT2-mediated reactivation of Lkb1 within established tumors. Lung tumors were initiated in KT;Lkb1XTR/XTR (non-restorable) and KT;Lkb1XTR/XTR;FLPo-ERT2 (restorable) mice with Lenti-Cre. Following tumor development, lung tumor-bearing were treated with either corn oil vehicle or tamoxifen for two weeks prior to isolating specifically neoplastic cells by FACS for single cell RNA-seq. Results: Single cell analysis revealed that the neoplastic epithelial compartment was composed of alveolar type I- and type II-like subpopulations, a Krt8+ transitional state, an actively proliferating subpopulations, and an indeterminate subpopulation partially resembling the alveolar type II-like identity. Dynamic inference analyses indicated that the indeterminate population represents an intermediate state along the alveolar type II to alveolar type I trans-differentiation trajectory. Notably, the indeterminate cluster was more proliferative than the alveolar type II-like subpopulation and exhibited higher expression of Sox9, which is a marker of distal lung epithelial progenitors. There was a marked shift in the epithelial compartment from the indeterminate state to alveolar type II epithelial-like identity in response to Lkb1 restoration. Conclusions: LKB1 governs the transition between a proliferative progenitor-like population and mature alveolar type II-like identity within oncogenic KRAS-driven lung tumors

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Dipeptidyl peptidase 4 restoration facilitates anti-tumor immunity in KRAS–LKB1–mutant lung cancer

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